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1.
Bioorg Chem ; 144: 107111, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38218068

RESUMEN

To mine fascinating molecules from the rhizomes of Atractylodes chinensis, the known molecular formula of atrachinenin A was used as a bait to search LC-HRMS data in different subfractions. Sixteen new meroterpenoids, atrachinenins D-S (1-16) including three unprecedented carbon skeletons (1-5) and eleven new oxygen-bridged hybrids (6-16) were obtained by the targeted isolation. Their structures and absolute configurations were elucidated by the spectroscopic data and electronic circular dichroism (ECD) calculations. The isolated compounds were evaluated for their inhibitory activity of NO production and compounds 1, 4, 8, and 13 showed moderate anti-inflammatory activity. The proposed biosynthetic pathways of 1-5 were also discussed.


Asunto(s)
Atractylodes , Atractylodes/química , Hidroquinonas , Antiinflamatorios , Dicroismo Circular , Estructura Molecular
2.
Br J Haematol ; 203(4): 599-613, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37666675

RESUMEN

Patients with multiple myeloma (MM) with chromosome 1q21 Gain (1q21+) are clinically and biologically heterogeneous. 1q21+ in the real world actually reflects the prognosis for gain/amplification of the CKS1B gene. In this study, we found that the copy number of prune exopolyphosphatase 1 (PRUNE1), located on chromosome 1q21.3, could further stratify the prognosis of MM patients with 1q21+. Using selected reaction monitoring/multiple reaction monitoring (SRM/MRM) analysis, liquid chromatography-tandem mass spectrometry (LC-MS/MS), transmission electron microscopy (TEM), confocal fluorescence microscopy, calculation of adenosine triphosphate (ATP), intracellular reactive oxygen species (ROS) and mitochondrial oxygen consumption rates (OCRs), we demonstrated for the first time that PRUNE1 promotes the proliferation and invasion of MM cells by stimulating purine metabolism, purine synthesis enzymes and mitochondrial functions, enhancing links between purinosomes and mitochondria. SOX11 was identified as a transcription factor for PRUNE1. Through integrated analysis of the transcriptome and proteome, CD73 was determined to be the downstream target of PRUNE1. Furthermore, it has been determined that dipyridamole can effectively suppress the proliferation of MM cells with high-expression levels of PRUNE1 in vitro and in vivo. These findings provide insights into disease-causing mechanisms and new therapeutic targets for MM patients with 1q21+.


Asunto(s)
Mieloma Múltiple , Humanos , Cromatografía Liquida , Aberraciones Cromosómicas , Cromosomas Humanos Par 3 , Mieloma Múltiple/terapia , Pronóstico , Purinas , Espectrometría de Masas en Tándem
3.
Anal Chem ; 95(2): 686-694, 2023 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-36601728

RESUMEN

To date, the extremely high polarity and poor signal intensity of macromolecular nucleic acids are greatly impeding the progress of mass spectrometry technology in the quality control of nucleic acid drugs and the characterization of DNA oxidation and RNA modifications. We recently described a general N-(tert-butyldimethylsilyl)-N-methyl-trifluoroacetamide (MTBSTFA) labeling method for oligonucleotide determination and applied it to the full-range profiling of tRNA in vitro and in vivo studies for the first time. The primary advantages of this method include strong retention, no observable byproducts, predictable and easily interpreted MS2 data, and the circumvention of instrument harmful reagents that were necessary in previous methods. Selective labeling of N-(tert-butyldimethylsilyl)-N-methyl-trifluoroacetamide to the terminal phosphate groups of oligonucleotides endows it broadly applicable for DNA/RNA profiling. Moreover, the improvement of sequence coverage was achieved in yeast tRNAphe(GAA) analysis owing to this method's good detection capability of 1-12 nucleotides in length. We also extended this strategy to determine the abundance of modified bases and discover new modifications via digesting RNA into single-nucleotide products, promoting the comprehensive mapping of RNA. The easy availability of derivatization reagent and the simple, rapid one-step reaction render it easy to operate for researchers. When applied in characterizing tRNAs in HepG2 cells and rats with nonalcoholic fatty liver disease, a fragment of U[m1G][m2G], specific for tRNAAsn(QUU) in cells, was significantly upregulated, indicating a possible clue to nonalcoholic fatty liver disease pathogenesis.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Ácidos Nucleicos , Animales , Ratas , Oligonucleótidos , ARN , ARN de Transferencia , Nucleótidos
4.
J Virol ; 96(6): e0214121, 2022 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-35044216

RESUMEN

Due to the high mutation rate of influenza virus and the rapid increase of drug resistance, it is imperative to discover host-targeting antiviral agents with broad-spectrum antiviral activity. Considering the discrepancy between the urgent demand of antiviral drugs during an influenza pandemic and the long-term process of drug discovery and development, it is feasible to explore host-based antiviral agents and strategies from antiviral drugs on the market. In the current study, the antiviral mechanism of arbidol (ARB), a broad-spectrum antiviral drug with potent activity at early stages of viral replication, was investigated from the aspect of hemagglutinin (HA) receptors of host cells. N-glycans that act as the potential binding receptors of HA on 16-human bronchial epithelial (16-HBE) cells were comprehensively profiled for the first time by using an in-depth glycomic approach based on TiO2-PGC chip-Q-TOF MS. Their relative levels upon the treatment of ARB and virus were carefully examined by employing an ultra-high sensitive qualitative method based on Chip LC-QQQ MS, showing that ARB treatment led to significant and extensive decrease of sialic acid (SA)-linked N-glycans (SA receptors), and thereby impaired the virus utilization on SA receptors for rolling and entry. The SA-decreasing effect of ARB was demonstrated to result from its inhibitory effect on sialyltransferases (ST), ST3GAL4 and ST6GAL1 of 16-HBE cells. Silence of STs, natural ST inhibitors, as well as sialidase treatment of 16-HBE cells, resulted in similar potent antiviral activity, whereas ST-inducing agent led to the diminished antiviral effect of ARB. These observations collectively suggesting the involvement of ST inhibition in the antiviral effect of ARB. IMPORTANCE This study revealed, for the first time, that ST inhibition and the resulted destruction of SA receptors of host cells may be an underlying mechanism for the antiviral activity of ARB. ST inhibition has been proposed as a novel host-targeting antiviral approach recently and several compounds are currently under exploration. ARB is the first antiviral drug on the market that was found to possess ST inhibiting function. This will provide crucial evidence for the clinical usages of ARB, such as in combination with neuraminidase (NA) inhibitors to exert optimized antiviral effect, etc. More importantly, as an agent that can inhibit the expression of STs, ARB can serve as a novel lead compound for the discovery and development of host-targeting antiviral drugs.


Asunto(s)
Indoles , Sialiltransferasas , Sulfuros , Antivirales/farmacología , Antivirales/uso terapéutico , Línea Celular , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Células Epiteliales , Glicómica , Hemaglutininas , Humanos , Indoles/farmacología , Indoles/uso terapéutico , Neuraminidasa/farmacología , Polisacáridos/metabolismo , Sialiltransferasas/antagonistas & inhibidores , Sulfuros/farmacología , Sulfuros/uso terapéutico
5.
J Org Chem ; 88(20): 14470-14486, 2023 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-37807762

RESUMEN

An I2-catalyzed oxidative cross-coupling of α-amino ketones with a wide range of alcohols is described. Using a combination of air and dimethyl sulfoxide (DMSO) as oxidants, the protocol allows an efficient synthesis of α-carbonyl N,O-acetals with high functional group tolerance and enables the late-stage introduction of α-amino ketones into biorelevant alcohols. Moreover, the present method can be used in the coupling of α-amino ketones with other kinds of nucleophiles, which demonstrates great generality for the functionalization of α-amino ketones. A preliminary mechanistic investigation suggests that C-H hydroxylation of α-amino ketones has been recognized as the key step followed by subsequent dehydration coupling.

6.
J Nat Prod ; 86(5): 1230-1239, 2023 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-37146221

RESUMEN

Amethystoidesic acid (1), a triterpenoid with an unprecedented 5/6/6/6 tetracyclic skeleton, and six undescribed diterpenoids, amethystoidins A-F (2-7), were isolated from the rhizomes of Isodon amethystoides along with 31 known di- and triterpenoids (8-38). Their structures were fully elucidated via extensive spectroscopic analysis including 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and electronic circular dichroism (ECD) calculations. Compound 1 is the first example of a triterpenoid possessing a rare ring system (5/6/6/6) derived from a contracted A-ring and the 18,19-seco-E-ring of ursolic acid. Compounds 6, 16, 21, 22, 24, and 27 significantly inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, which could be partly mediated by the downregulation of LPS-induced inducible nitric oxide synthase (iNOS) protein expression.


Asunto(s)
Isodon , Triterpenos , Isodon/química , Rizoma/metabolismo , Triterpenos/farmacología , Lipopolisacáridos/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/química , Óxido Nítrico , Estructura Molecular
7.
Nucleic Acids Res ; 49(1): 38-52, 2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33290562

RESUMEN

Acquired drug resistance is a major obstacle in cancer therapy. Recent studies revealed that reprogramming of tRNA modifications modulates cancer survival in response to chemotherapy. However, dynamic changes in tRNA modification were not elucidated. In this study, comparative analysis of the human cancer cell lines and their taxol resistant strains based on tRNA mapping was performed by using UHPLC-MS/MS. It was observed for the first time in all three cell lines that 4-demethylwyosine (imG-14) substitutes for hydroxywybutosine (OHyW) due to tRNA-wybutosine synthesizing enzyme-2 (TYW2) downregulation and becomes the predominant modification at the 37th position of tRNAphe in the taxol-resistant strains. Further analysis indicated that the increase in imG-14 levels is caused by downregulation of TYW2. The time courses of the increase in imG-14 and downregulation of TYW2 are consistent with each other as well as consistent with the time course of the development of taxol-resistance. Knockdown of TYW2 in HeLa cells caused both an accumulation of imG-14 and reduction in taxol potency. Taken together, low expression of TYW2 enzyme promotes the cancer survival and resistance to taxol therapy, implying a novel mechanism for taxol resistance. Reduction of imG-14 deposition offers an underlying rationale to overcome taxol resistance in cancer chemotherapy.


Asunto(s)
Resistencia a Antineoplásicos/genética , Paclitaxel/farmacología , Procesamiento Postranscripcional del ARN/genética , ARN Neoplásico/química , ARN de Transferencia de Fenilalanina/química , Células A549 , Secuencia de Bases , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Regulación hacia Abajo , Resistencia a Antineoplásicos/fisiología , Femenino , Regulación Enzimológica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Guanosina/análogos & derivados , Guanosina/química , Guanosina/metabolismo , Células HeLa , Humanos , Estructura Molecular , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Conformación de Ácido Nucleico , Neoplasias Ováricas/patología , ARN Neoplásico/fisiología , ARN de Transferencia de Fenilalanina/fisiología , Espectrometría de Masas en Tándem , Ensayo de Tumor de Célula Madre
8.
Molecules ; 28(12)2023 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-37375433

RESUMEN

Alcoholism is a worldwide health problem, and diseases caused by alcoholism are killing people every year. Amomum kravanh is a traditional Chinese medicine used to relieve hangovers. However, whether its bioactive components improve alcohol metabolism is not clear. In this study, ten new (amomumols A-J, 1-10) and thirty-five known (11-45) compounds were isolated from the fruits of Amomum kravanh by an activity-guided separation. Ten novel compounds were identified as four sesquiterpenoids (1-4), three monoterpene derivatives (5-7), two neolignans (8, 9), and a novel norsesquiterpenoid (10) with a new C14 nor-bisabolane skeleton. Their structures were determined by the comprehensive analysis of high-resolution electrospray ionization mass spectrometry (HRESIMS), nuclear magnetic resonance (NMR), and electronic circular dichroism (ECD) calculation. The effects of all isolated compounds on the activity of alcohol dehydrogenase were evaluated in vitro, and it was found that eight compounds (11, 12, 15, 18, 26, and 36-38) exhibited significant activation effects on the alcohol dehydrogenase at 50 µM.


Asunto(s)
Alcoholismo , Amomum , Humanos , Frutas/química , Amomum/química , Alcohol Deshidrogenasa , Monoterpenos/química
9.
Chin Chem Lett ; 34(1): 107701, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35911611

RESUMEN

The SARS­CoV­2 virus is released from an infectious source (such as a sick person) and adsorbed on aerosols, which can form pathogenic microorganism aerosols, which can affect human health through airborne transmission. Efficient sampling and accurate detection of microorganisms in aerosols are the premise and basis for studying their properties and evaluating their hazard. In this study, we built a set of sub-micron aerosol detection platform, and carried out a simulation experiment on the SARS­CoV­2 aerosol in the air by wet-wall cyclone combined with immunomagnetic nanoparticle adsorption sampling and ddPCR. The feasibility of the system in aerosol detection was verified, and the influencing factors in the detection process were experimentally tested. As a result, the sampling efficiency was 29.77%, and extraction efficiency was 98.57%. The minimum detection limit per unit volume of aerosols was 250 copies (102 copies/mL, concentration factor 2.5).

10.
Chin Chem Lett ; : 108378, 2023 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-37362323

RESUMEN

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 has negatively affected people's lives and productivity. Because the mode of transmission of SARS-CoV-2 is of great concern, this review discusses the sources of virus aerosols and possible transmission routes. First, we discuss virus aerosol collection methods, including natural sedimentation, solid impact, liquid impact, centrifugal, cyclone and electrostatic adsorption methods. Then, we review common virus aerosol detection methods, including virus culture, metabolic detection, nucleic acid-based detection and immunology-based detection methods. Finally, possible solutions for the detection of SARS-CoV-2 aerosols are introduced. Point-of-care testing has long been a focus of attention. In the near future, the development of an instrument that integrates sampling and output results will enable the real-time, automatic monitoring of patients.

11.
Gut ; 71(4): 734-745, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34006584

RESUMEN

OBJECTIVE: Programmed death 1 and its ligand 1 (PD-1/PD-L1) immunotherapy is promising for late-stage lung cancer treatment, however, the response rate needs to be improved. Gut microbiota plays a crucial role in immunotherapy sensitisation and Panax ginseng has been shown to possess immunomodulatory potential. In this study, we aimed to investigate whether the combination treatment of ginseng polysaccharides (GPs) and αPD-1 monoclonal antibody (mAb) could sensitise the response by modulating gut microbiota. DESIGN: Syngeneic mouse models were administered GPs and αPD-1 mAb, the sensitising antitumour effects of the combination therapy on gut microbiota were assessed by faecal microbiota transplantation (FMT) and 16S PacBio single-molecule real-time (SMRT) sequencing. To assess the immune-related metabolites, metabolomics analysis of the plasma samples was performed. RESULTS: We found GPs increased the antitumour response to αPD-1 mAb by increasing the microbial metabolites valeric acid and decreasing L-kynurenine, as well as the ratio of Kyn/Trp, which contributed to the suppression of regulatory T cells and induction of Teff cells after combination treatment. Besides, the microbial analysis indicated that the abundance of Parabacteroides distasonis and Bacteroides vulgatus was higher in responders to anti-PD-1 blockade than non-responders in the clinic. Furthermore, the combination therapy sensitised the response to PD-1 inhibitor in the mice receiving microbes by FMT from six non-responders by reshaping the gut microbiota from non-responders towards that of responders. CONCLUSION: Our results demonstrate that GPs combined with αPD-1 mAb may be a new strategy to sensitise non-small cell lung cancer patients to anti-PD-1 immunotherapy. The gut microbiota can be used as a novel biomarker to predict the response to anti-PD-1 immunotherapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Microbioma Gastrointestinal , Neoplasias Pulmonares , Panax , Animales , Anticuerpos Monoclonales/farmacología , Apoptosis , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/terapia , Muerte Celular , Microbioma Gastrointestinal/fisiología , Humanos , Factores Inmunológicos/farmacología , Inmunoterapia/métodos , Quinurenina/farmacología , Ligandos , Neoplasias Pulmonares/terapia , Ratones , Panax/metabolismo , Polisacáridos/farmacología , Triptófano/farmacología
12.
Pharmacol Res ; 178: 106154, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35248698

RESUMEN

Alzheimer's disease (AD) is a neurodegenerative disease associated with aging, and the number of people affected is rapidly increasing. Abnormally hyperphosphorylated tau filaments and extracellular deposits of amyloid ß-peptides (Aß) fibrils are two important pathological hallmarks of AD. Currently, stopping the production of Aß and blocking its aggregation is the main strategy for the treatment of AD. Turmeric is effective in treating neurodegenerative diseases, but there is no effective way to identify active compounds from their complicated chemical compositions. Instead of using conventional extraction and separation methods with low efficiency and time-consuming, our group tried to use atomic materials in high-throughput chemical screening due to their structural characteristics and the unique advantages of surface atomic. Herein, a novel atomic zinc sites with hierarchical porous carbon (Zn-HPC) was synthesized to quickly screen potential inhibitors of Aß aggregation in turmeric. As-combined Aß@Zn-HPC demonstrates superior storage stability and high selectivity, outperforming the most reported supporters for ligand fishing. Five compounds with strong affinity on Aß@Zn-HPC were selected by high-performance liquid chromatography-hybrid linear ion trap/orbitrap mass spectrometer after incubation with turmeric extract. Finally, it was shown that curcumin and bisdemethoxycurcumin can inhibit Aß aggregation by using thioflavin-T fluorescence assay and biolayer interferometry. A new application for the accurate identification of Aß aggregation inhibitors from turmeric were developed based on the active compounds possessing binding affinity to Aß to inhibit its aggregation. The developed method could provide a promising tool for efficient drug discovery from natural product resources.


Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Carbono , Humanos , Porosidad , Zinc/uso terapéutico
13.
Nano Lett ; 21(19): 8151-8159, 2021 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-34586821

RESUMEN

Differentiation of bone marrow derived mesenchymal stem cells (BMSCs) into functional neural cells has been widely investigated for treating neural diseases. However, the limited neural differentiation of BMSCs remains a big challenge to overcome. Herein, for the first time, ginseng-derived exosomes (G-Exos) were demonstrated to have excellent efficiency in stimulating the neural differentiation of BMSCs by transferring the incorporated miRNAs to BMSCs efficiently. In vivo, a photo-cross-linkable hydrogel with chemokine and G-Exos loaded shows strong efficacy in recruiting and directing the neural differentiation of BMSCs in the program. G-Exos were demonstrated to be promising nanoplatforms in transferring plant-derived miRNAs to mammalian stem cells for neural differentiation both in vitro and in vivo, possessing great potential in neural regenerative medicine.


Asunto(s)
Exosomas , Células Madre Mesenquimatosas , MicroARNs , Animales , Diferenciación Celular , Hidrogeles , MicroARNs/genética
14.
Int J Mol Sci ; 23(24)2022 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-36555386

RESUMEN

Parasitic helminths continue to pose problems in human and veterinary medicine, as well as in agriculture. Semen pharbitidis, the seeds of Pharbitis nil (Linn.) Choisy (Convolvulaceae), is a well-known traditional Chinese medicinal botanical preparation widely used for treating intestinal parasites in China owing to its desirable efficacy. However, the anthelmintic compounds in Semen pharbitidis and their mechanism of action have not been investigated yet. This study aimed to identify the compounds active against helminths from Semen pharbitidis, and to establish the mechanism of action of these active compounds. Bioassay-guided fractionation was used to identify the anthelmintic compounds from Semen pharbitidis. The anthelmintic assay was performed by monitoring Caenorhabditis elegans (C. elegans) motility with a WMicrotracker instrument. Active compounds were identified by high-resolution mass spectrometry. Several (analogues of) fragments of the anthelmintic compounds were purchased and tested to explore the structure-activity relationship, and to find more potent compounds. A panel of C. elegans mutant strains resistant to major currently used anthelmintic drugs was used to explore the mechanism of action of the active compounds. The bioassay-guided isolation from an ethanol extract of Semen pharbitidis led to a group of glycosides, namely pharbitin (IC50: 41.0 ± 9.4 µg/mL). Hit expansion for pharbitin fragments yielded two potent analogues: 2-bromohexadecanoic acid (IC50: 1.6 ± 0.7 µM) and myristoleic acid (IC50: 35.2 ± 7.6 µM). One drug-resistant mutant ZZ37 unc-63 (x37) demonstrated a ~17-fold increased resistance to pharbitin compared with wild-type worms. Collectively, we provide further experimental scientific evidence to support the traditional use of Semen pharbitidis for the treatment of intestinal parasites. The anthelmintic activity of Semen pharbitidis is due to pharbitin, whose target could be UNC-63 in C. elegans.


Asunto(s)
Antihelmínticos , Extractos Vegetales , Animales , Humanos , Extractos Vegetales/química , Caenorhabditis elegans , Semillas , Antihelmínticos/farmacología , Antihelmínticos/química , Glicósidos/farmacología , Bioensayo/métodos
15.
Anal Chem ; 93(3): 1423-1432, 2021 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-33382261

RESUMEN

Transfer RNAs (tRNAs) are the most heavily modified RNA species. Liquid chromatography coupled with mass spectrometry (LC-MS/MS) is a powerful tool for characterizing tRNA modifications, which involves pretreating tRNAs with base-specific ribonucleases to produce smaller oligonucleotides amenable to MS. However, the quality and quantity of products from base-specific digestions are severely impacted by the base composition of tRNAs. This often leads to a loss of sequence information. Here, we report a method for the full-range profiling of tRNA modifications at single-base resolution by combining site-specific RNase H digestion with the LC-MS/MS and RNA-seq techniques. The key steps were designed to generate high-quality products of optimal lengths and ionization properties. A linear correlation between collision energies and the m/z of oligonucleotides significantly improved the information content of collision-induced dissociation (CID) spectra. False positives were eliminated by up to 95% using novel inclusion criteria for collecting a census of modifications. This method is illustrated by the mapping of mouse mitochondrial tRNAHis(GUG) and tRNAVal(UAC), which were hitherto not investigated. The identities and locations of the five species of modifications on these tRNAs were fully characterized. This approach is universally applicable to any tRNA species and provides an experimentally realizable pathway to the de novo sequencing of post-transcriptionally modified tRNAs with high sequence coverage.


Asunto(s)
ARN de Transferencia/metabolismo , Animales , Cromatografía Liquida , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/química , Mitocondrias/metabolismo , ARN de Transferencia/análisis , Espectrometría de Masas en Tándem
16.
Org Biomol Chem ; 19(43): 9448-9459, 2021 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-34693412

RESUMEN

A C-H bond cleavage-enabled aerobic ring-opening reaction of 2-aminobenzofuran-3(2H)-ones formed in situ by hemiacetals with a variety of amines is reported. This simple one-pot reaction provides an alternative approach to obtain o-hydroxyaryl glyoxylamides in excellent yields of up to 97%. Alkylamines react with hemiacetals via a catalyst-free dehydration condensation to generate 2-aminobenzofuran-3(2H)-ones. The in situ formed semicyclic N,O-acetals undergo the same amine-initiated C-H bond hydroxylation in air under mild conditions to afford ring-opening products. Similarly, arylamines were investigated as substrates for a two-step tandem process involving a DPP-catalyzed condensation followed by a Et2NH-mediated C-H hydroxylation. Unlike the previously reported functionalization of N,O-acetals via a C-O or C-N cleavage, the aerobic oxidative C-H hydroxylation in this reaction, which is promoted by using stoichiometric amounts of alkylamines as both a Lewis base and a reductant at room temperature under atmospheric air, proceeds via α-carbonyl-stabilized carbanion intermediates from the C-H cleavage of N,O-acetals.

17.
Exp Cell Res ; 390(2): 111928, 2020 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-32156599

RESUMEN

Podocyte injury leads to impaired filtration barrier function of the kidney that underlies the pathophysiology of idiopathic nephrotic syndrome (INS), the most common NS occurring in children. The heat shock protein 90 (Hsp90) is involved in the regulation of apoptosis in a variety of cell types, however, little is known about its role in podocytes and whether it associated with NS. Here, we show that Hsp90 is upregulated in glomeruli podocytes from mice with adriamycin (ADR)-induced nephropathy, and that it is also upregulated in an immortalized podocyte cell line treated with ADR in vitro, together suggesting an association of Hsp90 upregulation in podocytes with NS pathogenesis. Functionally, Hsp90 inhibition with PU-H71 aggravates ADR-induced podocyte apoptosis and worsens the impairment of filtration barrier function. Mechanistically, Hsp90 inhibition with PU-H71 enhances the activation of intrinsic apoptotic pathway, and moreover, blockade of podocyte apoptosis with zVAD-fmk (aVAD), a pan-caspase inhibitor, abrogates effects of Hsp90 inhibition on filtration barrier function of ADR-treated podocytes, thus demonstrating that Hsp90 inhibition aggravates ADR-induced podocyte injury through intrinsic apoptosis pathway. In sum, this study reveals a detrimental role of Hsp90 inhibition in podocyte injury, which may offer it as a potential therapeutic target in NS therapy.


Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Doxorrubicina/administración & dosificación , Proteínas HSP90 de Choque Térmico/genética , Síndrome Nefrótico/genética , Podocitos/efectos de los fármacos , Clorometilcetonas de Aminoácidos/farmacología , Animales , Apoptosis/genética , Benzodioxoles/farmacología , Caspasa 3/genética , Caspasa 3/metabolismo , Caspasa 9/genética , Caspasa 9/metabolismo , Línea Celular , Citosol/efectos de los fármacos , Citosol/metabolismo , Regulación de la Expresión Génica , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Síndrome Nefrótico/inducido químicamente , Síndrome Nefrótico/metabolismo , Síndrome Nefrótico/patología , Podocitos/metabolismo , Podocitos/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Purinas/farmacología , Transducción de Señal , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo
18.
Bioorg Chem ; 112: 104830, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33819736

RESUMEN

Fourteen new monoterpene-flavonoid conjugates including four monoterpene-conjugated chalcones (glabratins A-D, 1-4), seven monoterpene-conjugated dihydrochalcones (glabratins E-K, 5-11), and three monoterpene-conjugated flavanones (glabratins L-N, 12-14), together with four known analogues (15-18) were isolated from the aerial parts of Sarcandra glabra. The structures and the absolute configurations of these compounds were elucidated by the spectroscopic data, single-crystal X-ray diffraction, and electronic circular dichroism (ECD) calculations. Compounds 1, 4-6, 9-14, and 18 showed obvious cell autophagy-inducing activities at 25 µM in HEK293 cells. Furthermore, the bioassay results also showed that 18 induced cell autophagy in a dose dependent manner. Our findings revealed a rare class of monoterpene-flavonoid conjugates in nature and firstly reported their autophagy-inducing activities.


Asunto(s)
Autofagia/efectos de los fármacos , Flavonoides/farmacología , Magnoliopsida/química , Monoterpenos/farmacología , Extractos Vegetales/farmacología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Flavonoides/química , Flavonoides/aislamiento & purificación , Células HEK293 , Humanos , Estructura Molecular , Monoterpenos/química , Monoterpenos/aislamiento & purificación , Método de Montecarlo , Componentes Aéreos de las Plantas/química , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Relación Estructura-Actividad
19.
Bioorg Chem ; 109: 104740, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33626453

RESUMEN

Six new non-classical cardenolides (1-6), and seventeen known ones (7-23) were isolated from Calotropis gigantea. All cardenolides showed inhibitory effect on hypoxia inducible factor-1 (HIF-1) transcriptional activity with IC50 of 8.85 nM-16.69 µM except 5 and 7. The novel 19-dihydrocalotoxin (1) exhibited a comparable HIF-1 inhibitory activity (IC50 of 139.57 nM) to digoxin (IC50 of 145.77 nM), a well-studied HIF-1 inhibitor, and 11, 12, 14, 16 and 19 presented 1.4-15.4 folds stronger HIF-1 inhibition than digoxin. 1 and 11 showed a dose-dependent inhibition on HIF-1α protein, which led to their HIF-1 suppressing effects. Compared with LO2 and H9c2 normal cell lines, both 1 and 11 showed selective cytotoxicity against various cancer cell lines including HCT116, HeLa, HepG2, A549, MCF-7, A2780 and MDA-MB-231. Moreover, a comprehensive structure-activity relationship was concluded for these non-classical cardenolides as HIF-1 inhibitors, which may shed some light on the rational design and development of cardenolide-based anticancer drugs.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Calotropis/química , Cardenólidos/farmacología , Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Extractos Vegetales/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Cardenólidos/química , Cardenólidos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Conformación Molecular , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Relación Estructura-Actividad
20.
Sensors (Basel) ; 21(1)2021 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-33406689

RESUMEN

Owing to insufficient illumination of the space station, the image information collected by the intelligent robot will be degraded, and it will not be able to accurately identify the tools required for the robot's on-orbit maintenance. This situation increases the difficulty of the robot's maintenance in a low-illumination environment. We proposes a novel enhancement method for images under low-illumination, namely, a deep learning algorithm based on the combination of deep convolutional and Wasserstein generative adversarial networks (DC-WGAN) in CIELAB color space. The original low-illuminance image is converted from the RGB space to the CIELAB color space which is relatively close to human vision, to accurately estimate the illumination image, and effectively reduce the effect of uneven illumination. DC-WGAN is applied to enhance the brightness component by increasing the width of the generation network to obtain more image features. Subsequently, the LAB is converted into RGB space to obtain the final enhanced image. The feasibility of the algorithm is verified by experiments on low-illuminance image under general, special, and actual conditions and comparing the experimental results with four commonly used algorithms. This study lays a technical foundation for robot target recognition and on-orbit maintenance in a space environment.

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